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AIDS-Related Lymphoma Treatment (PDQ®)

Table of Contents

General Information About AIDS-Related Lymphoma

Background and Definitions

The AIDS was first described in 1981, and the first definitions included certain opportunistic infections, Kaposi sarcoma, and central nervous system (CNS) lymphomas. In 1984, a multicenter study described the clinical spectrum of non-Hodgkin lymphomas (NHLs) in the populations at risk for AIDS.[1] In 1985 and 1987, the Centers for Disease Control and Prevention (CDC) revised the definition of AIDS to include human immunodeficiency virus (HIV)-infected patients who had aggressive B-cell NHL. The incidence of NHL has increased in an almost parallel course with the AIDS epidemic and accounts for 2% to 3% of newly diagnosed AIDS cases.[2]

Histology

Pathologically, AIDS-related lymphomas are comprised of a narrow spectrum of histologic types consisting almost exclusively of B-cell tumors of aggressive type. These include the following:

Diffuse large B-cell lymphoma.

B-cell immunoblastic lymphoma.

Small noncleaved lymphoma, either Burkitt or Burkitt-like.

The HIV-associated lymphomas can be categorized into the following:

Aggressive B-cell lymphoma.

Primary central nervous system lymphoma (PCNSL), which represents 20% of all NHL cases in AIDS patients.

Primary effusion lymphoma.

Plasmablastic multicentric Castleman disease.

Hodgkin lymphoma.

Primary effusion lymphoma

Primary effusion lymphoma has been associated with Kaposi sarcoma-associated herpes-virus/human herpes virus type-8 (KSHV/HHV-8).[3,4] Primary effusion lymphoma presents as a liquid phase spreading along serous membranes in the absence of masses or adenopathy.[3] In addition to HHV-8, many cases are also associated with Epstein-Barr virus. Extension of lymphoma from the effusion to underlying tissue may occur. Plasmablastic multicentric Castleman disease is also associated with a coinfection of KSHV/HHV-8 and HIV.[5,6] Patients typically present with fever, night sweats, weight loss, lymphadenopathy, and hepatosplenomegaly. Patients may progress to primary effusion lymphoma or to plasmablastic or anaplastic large cell lymphoma. Anecdotal responses to rituximab, an anti-CD20 monoclonal antibody, have been reported.[5][Level of evidence: 3iiiDiv]

Incidence and Prevention

An international database of 48,000 HIV-seropositive individuals from the United States, Europe, and Australia found a 42% decline in the incidence of NHLs from 1997 to 1999 compared with 1992 to 1996, both for PCNSL and for systemic lymphoma.[7] The introduction of highly active antiretroviral therapy (HAART) is the proposed explanation for this decline.[8] The diagnosis of AIDS precedes the onset of NHL in approximately 57% of the patients, but in 30% of the patients the diagnosis of AIDS is made at the time of the diagnosis of NHL and HIV positivity.[9] The geographic distribution of these lymphomas is also similar to the geographic spread of AIDS. Unlike Kaposi sarcoma, which has a predilection for homosexual men and appears to be on the decline in incidence, all risk groups appear to have an excess number of NHLs; these risk groups include intravenous drug users and children of HIV-positive individuals.

Clinical Presentation

In general, the clinical setting and response to treatment of patients with AIDS-related lymphoma is very different from that of the non-HIV patients with lymphoma. The HIV-infected individual with aggressive lymphoma usually presents with advanced-stage disease that is frequently extranodal.[10]

Common extranodal sites include the following:

Bone marrow.

Liver.

Meninges.

Gastrointestinal tract.

Very unusual sites are also characteristic and include the following:

Anus.

Heart.

Bile duct.

Gingiva.

Muscles.

The clinical course is more aggressive, and the disease is both more extensive and less responsive to chemotherapy. Immunodeficiency and cytopenias, common in these patients at the time of initial presentation, are exacerbated by the administration of chemotherapy. Treatment of the malignancy increases the risk of opportunistic infections that, in turn, further compromise the delivery of adequate treatment.

Prognosis and Survival

Prognoses of patients with AIDS-related lymphoma have been associated with the following:[11]

Patients with AIDS-related PCNSL appear to have more severe underlying HIV-related disease than do patients with systemic lymphoma. In one report, this severity was evidenced by patients with PCNSL having a higher incidence of prior AIDS diagnoses (73% vs. 37%), lower median number of CD4 lymphocytes (30/dL vs. 189/dL), and a worse median survival time (2.5 months vs. 6.0 months).[12] This report also showed that patients with poor risk factors—defined as Karnofsky performance status less than 70%, history of prior AIDS diagnosis, and bone marrow involvement—had a median survival time of 4.0 months compared with a good prognosis group without any of these risk factors, who had a median survival time of 11.3 months.

In another report (NIAID-ACTG-142), prognostic factors were evaluated in a group of 192 patients with newly diagnosed AIDS-related lymphoma who were randomly assigned to receive either low-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) or standard dose m-BACOD with granulocyte-macrophage colony-stimulating factor.[13] No differences existed between these two treatments in terms of efficacy for disease-free survival, median survival, or risk ratio for death.[13][Level of evidence: 1iiA] On multivariate analysis, factors associated with decreased survival included age older than 35 years, history of intravenous drug use, stage III or stage IV disease, and CD4 counts of less than 100 cells/mm3. The median survival rates were 46 weeks for patients with one or no risk factors, 44 weeks for patients with two risk factors, and 18 weeks for patients with three or more risk factors. The International Prognostic Index may also be predictive for survival.[14-16] In a multicenter cohort study of 203 patients, in a multivariable Cox model, response to HAART was independently associated with prolonged survival (relative hazard = 0.32; 95% confidence interval, 0.16–0.62).[17][Level of evidence: 3iiiDii]

HIV-associated Hodgkin lymphoma

Multiple reviews of Hodgkin lymphoma occurring in patients at risk for AIDS have been done;[18,19] however, Hodgkin lymphoma is still not part of the CDC definition of AIDS because of no clear demonstration of its increased incidence in conjunction with HIV, as is the case for aggressive NHL. The CDC, in conjunction with the San Francisco Department of Public Health, has reported a cohort study in which HIV-infected men had an excess risk that was attributable to the HIV infection of 19.3 cases of Hodgkin lymphoma per 100,000 person-years and 224.9 cases of NHL per 100,000 person-years. Although an excess incidence of Hodgkin lymphoma was found in HIV-infected homosexual men in this report, additional epidemiologic studies will be needed before the CDC will reconsider Hodgkin lymphoma as an HIV-associated malignancy.[20]

HIV-associated Hodgkin lymphoma presents in an aggressive fashion, often with extranodal or bone marrow involvement.[18,19,21] A distinctive feature of HIV-associated Hodgkin lymphoma is the lower frequency of mediastinal adenopathy compared with non-HIV-associated Hodgkin lymphoma. Most patients in these series had either mixed cellularity or lymphocyte-depleted Hodgkin lymphoma, expression of Epstein-Barr virus-associated proteins in Reed-Sternberg cells, B symptoms, and a median CD4 lymphocyte count of 300/dL or less.[22] In a retrospective multicenter review of 62 patients, those receiving HAART with chemotherapy had a 74% 2-year overall survival (OS) versus a 30% OS for those not receiving HAART (P < .001).[23][Level of evidence: 3iiiA]

Related Summaries

Note: Other PDQ summaries containing information about AIDS-related lymphoma include the following:

Cellular Classification of AIDS-Related Lymphoma

Pathologically, AIDS-related lymphomas are comprised of a narrow spectrum of histologic types consisting almost exclusively of B-cell tumors of aggressive type. These include the following:

Diffuse large B-cell lymphoma.

B-cell immunoblastic lymphoma.

Small noncleaved lymphoma, either Burkitt or Burkitt-like.

All three pathologic types are equally distributed and represent aggressive disease.

AIDS-related lymphomas, though usually of B-cell origin as demonstrated by immunoglobulin heavy-chain gene rearrangement studies, have also been shown to be oligoclonal and polyclonal as well as monoclonal in origin. Although human immunodeficiency virus (HIV) does not appear to have a direct etiologic role, HIV infection does lead to an altered immunologic milieu. HIV generally infects T lymphocytes whose loss of regulation function leads to hypergammaglobulinemia and polyclonal B-cell hyperplasia. B cells are not the targets of HIV infection. Instead, Epstein-Barr virus (EBV) is thought to be at least a cofactor in the etiology of some of these lymphomas. The EBV genome has been detected in varying numbers of patients with AIDS-related lymphomas; molecular analysis suggests that the cells were infected before clonal proliferation began.[1] EBV is detected in 30% of patients with small, noncleaved lymphomas and in 80% of patients with diffuse, large cell lymphomas. The rare, primary effusion lymphoma consistently harbors human herpes virus type-8 and frequently contains EBV.[2] HIV-related T-cell lymphomas have also been identified and appear to be associated with EBV infection.[3]

Involvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I).

OR

Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma).

II

Involvement of two or more lymph node regions on the same side of the diaphragm (II).

OR

Localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of regions involved may be indicated by a subscript Arabic numeral, for example, II3

III

Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, IIIS). Splenic involvement is designated by the letter S.

IV

Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.

OR

Isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.

The Ann Arbor staging system is commonly used for patients with NHL.[1,2] In this system, stage I, II, III, and IV NHL can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without. The B designation is given to patients with any of the following symptoms:

Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.

Occasionally, specialized staging systems are used. The physician should be aware of the system used in a specific report.

The E designation is used when extranodal lymphoid malignancies arise in tissues separate from, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Table 2. Notation for Identification of Sites

N = nodes

H = liver

L = lung

M = marrow

S = spleen

P = pleura

O = bone

D = skin

Current practice assigns a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of invasive procedures beyond the initial biopsy.

For example, on percutaneous biopsy, a patient with inguinal adenopathy and a positive lymphangiogram without systemic symptoms might be found to have involvement of the liver and bone marrow. The precise stage of such a patient would be CS IIA, PS IVA(H+)(M+).

A number of other factors that are not included in the above staging system are important for the staging and prognosis of patients with NHL. These factors include the following:

Age.

Performance status (PS).

Tumor size.

Lactate dehydrogenase (LDH) values.

The number of extranodal sites.

To identify subgroups of patients most likely to relapse, an international prognostic index was compiled for 2,031 patients with aggressive NHL.[3] After validation by several cancer centers (NCT00003150),[4,5] the major cooperative groups used this index in the design of new clinical trials. The model has been simple to apply, reproducible, and has predicted outcome even after patients have achieved a complete remission. The model has identified five significant risk factors prognostic of overall survival (OS): age (<60 years vs. >60 years), serum LDH (normal vs. elevated), PS (0 or 1 vs. 2–4), stage (stage I or stage II vs. stage III or stage IV), and extranodal site involvement (0 or 1 vs. 2–4).

Patients with two or more risk factors were shown to have a less than 50% chance of relapse-free and OS at 5 years. This study also identified patients at high risk of relapse based on specific sites of involvement, including bone marrow, central nervous system, liver, lung, and spleen. Patients at high risk of relapse may benefit from consolidation therapy or other approaches under clinical evaluation.[3] Molecular profiles of gene expression using DNA microarrays may help to stratify patients in the future for therapies directed at specific targets and to better predict survival after standard chemotherapy.[6,7]

Treatment Option Overview for AIDS-Related Lymphoma

The treatment of patients with AIDS-related lymphomas presents the challenge of integrating therapy appropriate for the stage and histologic subset of malignant lymphoma with the limitations imposed by HIV infection, which to date is a chronic incurable illness.[1] In addition to antitumor therapy, essential components of an optimal non-Hodgkin lymphoma treatment strategy include the following:[2]

Highly active antiretroviral therapy.

Prophylaxis for opportunistic infections.

Rapid recognition and treatment of intercurrent infections.

Patients with HIV positivity and underlying immunodeficiency have poor bone marrow reserve, which compromises the potential for drug dose intensity. Intercurrent opportunistic infection is a risk that may also lead to a decrease in drug delivery. Furthermore, chemotherapy itself compromises the immune system and increases the likelihood of opportunistic infection.

AIDS-Related Peripheral/Systemic Lymphoma

The treatment of AIDS-related lymphomas involves overcoming several problems. These are all aggressive lymphomas, which by definition are diffuse large cell/immunoblastic lymphoma or small noncleaved cell lymphoma. These lymphomas frequently involve the bone marrow and central nervous system (CNS) and, therefore, are usually in an advanced stage. In addition, the immunodeficiency of AIDS and the leukopenia that is commonly seen with human immunodeficiency virus (HIV) infection makes the use of immunosuppressive chemotherapy difficult.

A large number of retrospective studies and several prospective studies have been reported using regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD), and infusional cyclophosphamide, doxorubicin, and etoposide.[1-4] The patients who go into remission are more likely to have less disease, no bone marrow or CNS involvement, no prior AIDS-defining illness, and a better performance status. Patients at risk for subsequent CNS involvement include those with bone marrow involvement or those with Epstein-Barr virus identified in the primary tumor or in the cerebrospinal fluid (i.e., by polymerase chain reaction).[5-7] Intrathecal chemotherapy is usually considered for those patients at higher risk for CNS involvement.

Before the highly active, antiretroviral-therapy (HAART) era, a randomized trial of patients with HIV and either Burkitt lymphoma (BL) or diffuse large B-cell lymphoma (DLBCL) compared standard dose chemotherapy and growth factor support with reduced-dose chemotherapy.[1] No difference was found in overall survival (OS) between the two dose levels, and no difference was observed between the historic groups (BL and DLBCL); however, the median survival was equally poor at 6 to 7 months.[1][Level of evidence: 1iiA] The introduction of HAART has led to a marked reduction in opportunistic infections, prolonged survival with HIV infection, and a median OS for patients with AIDS-related lymphoma, which is comparable to the outcome in the nonimmunosuppressed population.[4,8-14][Level of evidence: 3iiiDiv] The use of HAART has also allowed the use of standard dose and even intensive chemotherapy regimens to be given with reasonable safety to patients with AIDS-related lymphomas, which is comparable to the outcome in non-HIV patients.[3,4,13-16]

In a retrospective review of 363 patients with HIV-associated lymphoma, survival of patients with HIV-DLBCL improved in the HAART era, but survival of similarly treated patients with HIV-BL remained poor.[17][Level of evidence: 3iiiDiv] Future studies will evaluate if more intensive chemotherapy appropriate for non-HIV patients with BL results in better outcomes for patients with HIV-BL.[17] A prospective randomized comparison (AMC-010) of rituximab plus CHOP (R-CHOP) versus CHOP in 150 patients with HIV-DLBCL and HIV-BL showed no difference in OS; treatment-related infectious deaths occurred in 14% of patients who received R-CHOP versus 2% of patients who received CHOP alone (P = .035).[18][Level of evidence: 1iiA] A Cochrane meta-analysis published in 2009 evaluated 857 patients in four randomized clinical trials; no clinical conclusions regarding the optimal regimen could be reached as a result of varying interventions and the lack of adequately powered trials with a low risk of bias.[19]

Highly selected patients with resistant or relapsed lymphoma after first-line chemotherapy and with continued responsiveness to HAART underwent second-line chemotherapy followed by high-dose therapy and autologous peripheral stem cell transplantation. Long-term survivors have been reported anecdotally for these highly selected patients who relapsed.[20-23][Level of evidence: 3iiiDiv]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with AIDS-related peripheral/systemic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

AIDS-Related Primary Central Nervous System Lymphoma (PCNSL)

Until the 1980s, primary central nervous system lymphoma (PCNSL) was a rare disease. PCNSL has increased dramatically in association with AIDS.[1] PCNSL accounts for approximately 0.6% of initial AIDS diagnoses and is the second most frequent central nervous system (CNS) mass lesion in adults with AIDS. As with other AIDS-related lymphomas, these are usually aggressive B-cell neoplasms, either diffuse large cell or diffuse immunoblastic non-Hodgkin lymphoma. Unlike AIDS-related systemic lymphomas, in which 30% to 50% of tumors are associated with Epstein-Barr virus (EBV), AIDS-related PCNSL has been reported to have a 100% association with EBV.[2] This percentage indicates a pathogenetic role for EBV in this disease. These patients usually have evidence of far-advanced AIDS, are severely debilitated, and present with focal neurologic symptoms such as seizures, changes in mental status, and paralysis.

Computed tomographic scans show contrast-enhancing mass lesions that may not always be distinguished from other CNS diseases, such as toxoplasmosis, that occur in AIDS patients.[3] Magnetic resonance imaging studies using gadolinium contrast may be a more useful initial diagnostic tool in differentiating lymphoma from cerebral toxoplasmosis or progressive multifocal leukoencephalopathy. Lymphoma tends to present with large lesions, which are enhanced by gadolinium. In cerebral toxoplasmosis, ring enhancement is very common, lesions tend to be smaller, and multiple lesions are seen.[4-6] Use of positron emission scanning has demonstrated an improved ability to distinguish PCNSL from toxoplasmosis.[7,8]

PSNCL has an increased uptake while toxoplasmosis lesions are metabolically inactive. Antibodies against toxoplasmosis may also be very useful because the vast majority of cerebral toxoplasmosis occur as a consequence of reactivity of a previous infection. If the IgG titer is less than 1:4, the disease is unlikely to be toxoplasmotic. A lumbar puncture may be useful to detect as many as 23% of patients with malignant cells in their cerebrospinal fluid (CSF). Evaluating the CSF for EBV DNA may be a useful lymphoma-specific tool since EBV is present in all patients with PCNSL. Despite all of these evaluations, however, the majority of patients with PCNSL require a pathologic diagnosis.[9-11] Diagnosis is made by biopsy. Sometimes, a biopsy is attempted only after failure of antibiotics for toxoplasmosis, which will produce clinical and radiographic improvement within 1 to 3 weeks in patients with cerebral toxoplasmosis.[12] PCNSL is often identified as a terminal manifestation of AIDS or on postmortem examination.

Radiation therapy alone has usually been used in this group of patients. With doses in the 35 Gy to 40 Gy range, median duration of survival has been only 72 to 119 days.[3,13,14] Survival is longer in younger patients with better performance status and the absence of opportunistic infection.[15] Most patients respond to treatment by showing partial improvement in neurologic symptoms. Autopsies have revealed that these patients die of opportunistic infections as well as tumor progression. Treatment of these patients is also complicated by other AIDS-related CNS infections, including subacute AIDS encephalitis, cytomegalovirus encephalitis, and toxoplasmosis encephalitis. Spontaneous remissions have been reported after highly active antiretroviral therapy.[16]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with AIDS-related primary CNS lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of AIDS-related lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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